N-(2-imino-2-phenylethyl)amines and a process for their preparation



United States Patent 3,068,236 N-(2-lMINO-2-PHENYLETHYL)AMINES AND A PROCESS FOR THEIR PREPARATION John Krapcho,'New Brunswick, NJ., assignor to Olin Mathieson Chemical Corporation, New Yorlr, N.Y., a

corporation of Virginia No Drawing. Filed Oct. 17, 1960, Ser. No. 62,897 7 Claims. (Cl. 260-2934) This invention relates to a new iminophenylethylamine derivatives and, more-particularly, to compounds of the general formula wherein R is hydrogen, lower alkyl (e.g., methyl, ethyl and isopropyl), halogen (e.g., chlorine and fluorine), halomethyl (e.g., trifluoromethyl), alkoxy (e.g., methoxy, ethoxy, propoxy and amyloxy), aryloxy (e.g., phenyloxy), hydroxy, amino, or dialkylamino (e.g., dimethylamino and diethylamino); R is hydrogen or acyl; R" and R are lower alkyl, phenyl, or, together with the carbon to which they are joined, constitute a cycloalkyl radical (e.g., cyclohexyl, cyclopentyl and cycloheptyl); and B is a basic, nitrogen-containing radical such as alkylamino, dialkylamino (e.g., dimethylamino and diethylamino), alkylaralkylamino, piperidyl (e.g., piperidino), alkylpiperidyl (e.g., 2, 3 and 4-methylpiperidino) dialkylpiperidyl (e.g., 2,4-, 2,6-, and 3,5-dimethylpiperidino); pyrrolidyl (e.g., pyrrolidino), alkylpyrrolidyl, dialkylpyrrolidyl, piperazinyl (e.g., piperazino), alkylpiperazinyl (e.g., 4-methylpiperazin'o), dialkylpiperazinyl, alkoxypiperazinyl and arylpiperazinyl (e.g., 4-phenylpiperazino); and the pharmaceutically acceptable acid-addition salts thereof.

Among the suitable acyl groups defined by R may be mentioned R-substituted alkanoyl (e.g., acetyl, dichloracetyl and propionyl), R-substituted alkenoyl (e.g., S-butenoyl), R-substituted alkadienoyl (e.g., sorboyl), R-sub stituted alkadienoyl, R-substituted aralkanoyl (e.g., phen' acetyl), R-substituted aralkcnoyl (e.g., cinnamoyl), R-substituted aroyl (e.g., benzoyl, p-chlorobenzoyl and naphthoyl), carbamyl, dialkylcarbamyl (e.g., dimethylcarbamyl and diethylcarbamyl), lower alkane sulfonyl (e.g., methanesulfonyl) and aryl sulfonyl (e.g., benzenesulfonyl), wherein R is as hereinbefore defined. The pre ferred compounds are those wherein R is hydrogen, R is acetyl or phenacetyl, R" and R' are lower alkyl and B is piperidino. I

Examples of suitable acid-addition salts of the free base compounds of this invention include the mineral acid salts, such as the hydrohalide (e.g., hydrochloride, hydrobromide and hydroiodide), the sulfate and the phosphate; and the organic acid salts, such as the citrate, tartrate, oxalate, ascorbate and succinate. Pharmacologically acceptable acids are, of course, employed where the salt form is prepared for therapeutic use.

The compounds of the present invention are prepared by a process which comprises reacting an R-substituted phenyl lithium with a nitrile of the formula l liC-GB wherein R, R" and R'" and B have the values herein- "ice before defined, and subjecting the resulting lithium complex to mild hydrolysis thereby providing an N-unsubstituted free base of the present invention of the formula 111! it Q The imino compounds of this formula are readily converted to the N-substituted derivatives by treatment with an acylating agent such as an acyl halide (R' halogen) or an acid anhydride (R') O, wherein R is an acyl group as hereinbefore defined.

The compounds of this invention are physiologically active substances having central nervous system activity. Thus, these compounds can be used as anorectic agents in the treatment and control of obesity. For such purposes the compounds of this invention are administered perorally with dosage adjusted for the particular activity of a given compound.

The following examples illustrate the invention (all temperatures given in degrees centigrade):

EXAMPLE 1 1-(2-lmino-I,1-DimethyI-2-Phenylethyl)Piperidine,

' Hydrochloride A suspension of 13.9 g. of lithium ribbon in 700 ml. of ether is treated with 157- g. of bromobenzene. The resulting solution of phenyl lithium is treated dropwise with a solution of 75.0 g. of a-piperidinoisobutyronitrile in 200 ml. of ether. The mixture is stirred] and refluxed for two hours, cooled and poured slowly into a mixture of a solution of 110 g. of ammonium chloride in 700 ml.

of water and 200 g. of ice. The mixture is shaken thoroughly and the aqueous phase then extracted with 300 ml. of ether, the ether extract dried over magnesium sulfate, filtered and evaporated. The residue is fractionated to give about 104 g. of pale yellow distillate; B.P. about 110-112 (0.2 mm.). 30 g. of this material is dissolved in 30 ml. of absolute alcohol and treated with one equivalent of alcoholic hydrogen chloride. The resulting solution is diluted to 400 ml. with ether, precipitating about 34 g. of colorless solid, M.P. about ll77. Recrystallization from 200 ml. of acetonitrile yields about 22 g. of 1-(2-imino l,l-dimethyl-Z-phenylethyl)piperidine, hydrochloride, having a melting point of about 175-177 EXAMPLE 2 1-(2-Acetylimino-1,l-Dimethyl-2-Phenylethyl)Piperidine, Hydrochloride EXAMPLE 3 1-(1,1-Dimethyl-2-Propionylimino-Z-Phenylethyl) Piperidine, Hydrochloride A solution of 46.0 g. of the imino compound from Example 1 is reacted with 18.5 g. of propionyl chloride in benzene solution as described in Example 2, yielding about 51.3 g. of solid, M.P. about 147-149. Recrystallization from 450 ml. of butanone followed by recrystallization from ml. of methanol-1300 ml. of ether yields about 31.7 g. of l-(1,l-dimethyl-2-propionylimino 2g-phenylethyl)piperidine, hydrochloride, having a melt ing point of about 149-150.

EXAMPLE 4 1- (1,]-DimcIhyI-Z-Phenacetylamino-Z-Phenylethyl) Piperidine, Hydrochloride Interaction of 40 g. of the imino compound from Example 1 with 27 g. of phenylacetyl chloride in benzene according to the procedure described in Example 2 yields about 62.5 g. of product, M.P. about 160-165. This material is crystallized twice from 250 ml. portions of isopropyl alcohol and then from 100 ml. methanol-1300 ml. of ether, yielding about 31.0 g. of l-(1,1-dimethyl-2- phenacetylimino-Z-phenylethyl)piperidine, hydrochloride, having a melting point of about 168.5-169.5.

EXAMPLE 5 l-(2-Cinnamoylimino-I,I-Dirnethyl-2 Phenylethyl) Piperidine, Hydrochloride Interaction of 34.7 g. of the irnino compound from Example 1 with 25 g. of cinnamoyl chloride in benzene according to procedure described in Example 2 gives about 26.6 g. of colorless crystalline hydrochloride of 1 (Z-einnamoylimino-l,I-dimethyLZ-phenylethyl)piperidine, having a melting point of about 175-l76.

EXAMPLE 6 1-(1,1-Dimcthyl-2-MethanesuIfonyIimino-Z-Phenylethyl) Piperidine, Hydrochloride Interaction of 33.5 g. of the imino compound from Example 1 with 16.5 g. of methanesulfonyl chloride in benzene according to the procedure of Example 2 yields about 30.2 g. of solid mtaerial, M.P. about 178-194. This material is dissolved in 150 ml. of ethanol and the resulting solution diluted with 650 ml. of ether, yielding about 18.7 g. of colorless material, M.P. about 210217. Two crystallizations from 125 ml. of ethanol, yields about 12.4 g. of 1-(1,1-dimethyl-Z-methane-sulfonylimino-2- phenylethyl)piperidine, hydrochloride, having a melting point of about 224-225.

EXAMPLEJ 1-(1,1-Dimethyl-Z-Benzenesulfonylimino-Z-Phenylethyl) Piperidinc Substitution of an equivalent amount of benzenesulfonyl chloride for the methanesulfonyl chloride employed in the above reaction gives the colorless, crystalline hydrochloride of 1-(1,l-dimethyl-2-benzenesulfonylimino-2- phenylethyl) piperidine.

EXAMPLE 8 1-(2-p-Chlorobenz0ylimino-I,1-Dimethyl-2-Phenylethyl) Piperdine H ydrochloride Interaction of 46.0 g. of the imino compound from Example 1 with 35.0 g. of p-chlorobenzoyl chloride in benzene according to the procedure in Example 2 yields the colorless crystalline hydrochloride of l-(2-p-chlorobenzoylimino-l,l-dimethyl-Z-phenylethyl)piperidine, hydrochloride.

EXAMPLE 9.

4 talline hydrochloride of 1-(2-dichloroacetylimino-1,l-dipmethyl-2-phenylethyl)piperidine hydrochloride.

EXAMPLE 11 l-[2-Imino-1,1-Dimethyl-2-(4-Meth0xyphenyl)Ethyl] Piperidine, Hydrochloride Following the procedure of Example 1 except for the substitution of an equivalent amount of 4-methoxyphenyl lithium for the phenyl lithium used therein, yields the product 1 LZ-imino-l,l-dimethyl-Z-(4-methoxyphenyl) ethyl]piperidine, hydrochloride.

Similarly, substitutions of the equivalent amounts of 4- methylphenyl lithium, 2-fiuorophenyl lithium, 3-trifiuorophenyl lithium, 2-phenoxyphenyl lithium, Z-hydroxyphenyl lithium, 4-aminophenyl lithium and 4-dimethylaminophenyl lithium yield, respectively, the hydrochlorides of the following products:

1- [Z-imino- 1, 1-dimethyl-2-(4-methylphenyl ethyl] piperidine,

1-[Z-imino-1,l-dimethyl-Z-(2-fluorophenyl) ethyl] piperidine,

1- [2-imino-1, l-dimethyl-2-( 3-trifluoromethylphenyl ethyl] piperidine,

l-[2-imino-l,1-dimethyl-2-(Z-phenoxyphenyl) ethyl] piperidine,

1-[2-imino-1,1-dimethyl2-(2-hydroxyphenyl) ethyl] piperidine,

1- [2-iminol, l-dimethyl-Z- 4-aminophenyl) ethyl] piperidine, and

1-[2-imino-1,1-dimethy1-2-(4-dimethylaminophenyl) ethyl] piperidine.

EXAMPLE 12 I (.Z-Imino-I ,1 -Dimethyl-2-Phcnylethyl -4-M ethyl- Piperazine PART A. 2-METHYL-2- (4-METHYL-1-PIPERAZINYL)- PROPIONITRILE A cold solution of g. of acetonecyanohydrin is treated portionwise with g. of l-methylpiperazine and then heated at 85-90 for two hours. The mixture is then refluxed for thirty minutes, after which it is fractionated giving about 137 g. of colorless distillate, B.P. about 85-90 (6 mm.). Crystallization of 131 g. of this material from 150 ml. of hexane, yields about g. of 2-methyl-2-(4-methyl-l-piperazinyl) propionitrile, having a melting point of about 58-60.

PART B. 1-(ammo-1,1-DIMETHYL2-PHENYLETHYL)- *t-METHYLPIPERAZINE A solution of 84 g. of material from Part A in 200 ml. of ether is added to 700 ml. of ethereal solution containing one equivalent of phenyl lithium and the reaction is then carried out by the procedure employed in Example 1, yielding about 87.8 g. of a nearly colorless product boiling at about 115-117" (0.2 mm.). Two crystallizations of 25 g. of this material from 25 ml. portions of hexane gives about 22 g. of 1-(2-imino-1,1-dimethyl-2- phenylethyl)-4-methylpiperazine, having a melting point of about 66-69.

EXAMPLE 13 I (2 Dimethylcarbamylimino 1,1 Dimethyl 2- Phenylethyl)-4-Methylpiperazine A solution of 25.0 g. of material from Part B of Exam- 1 ple 11 in 100 ml. of benzene is cooled and treated with 11.0 g. of dimethylcarbamyl chloride and the resulting solution refluxed for eight hours. After cooling, the solution is filtered, giving about 25.2 g. of the hydrochloride salt. 19.6 g. of this material is dissolved in 50 ml. of water and treated with 56 m1. of normal sodium hydroxide solution. The mixture is extracted three times with 200 ml. portions of ether, dried over magnesium sulfate, filtered and evaporated. The residue, upon trit-= 7 uration with hexane, gives about 15.7 g. of solid, M.P.

. about 97-100. Two crystallizations from 100 ml. per-- tions of hexane, yield about 13.5 g. of 1-(2-dimethylcarbamylimino 1,1 dimethyl 2 phenylethyl) 4 methylpiperazine, having a melting point of about 104-105.

EXAMPLE -14 1 -(2-Imino1,1-Dimethyl-2-Phenylethyl) 4-Phenylpiperazine PART A. 2-llETHYL-2- (4-PHENYL-1-PIPE RAZINYL) PROPIONITRILE Interaction of 61.0 g. of material of Part A with a solution of 50.4 g. of phenyl lithium in 1900 ml. of ether according to the procedure described in Example 1 gives about 76.8 g. of 1-(2-imino-l,1-dimethyl-2-phenylethyl)- 4-phenylpiperazine, M.P. about 85-90". Upon purification by recrystallization from 95% ethanol, the colorless product melts at about 93-94.

EXAMPLE l I-(Imino-I,1-Dimethyl-2-Phenylethyl)Pyrrolidine PART A. 2-METHYL-2-PYRROLIDINOPROPIONITRILE A mixture of 125 g. of pyrrolidine and 150 g. of acetonecyanohydrin is heated on a steam bath for three hours and then fractionated to give about 230 g. of 2-methyl-2- pyrrolidinopropionitrile, B.P. 67-70 (0.5 mm.).

PART B. 1-(2-IMINO-1,1-DIMETHYL-2-PHENYLETHYL)- PYRROLIDINE A solution of 230 g. of material from Part A is reacted with a solution of 279 g. of phenyl lithium in ether according to the procedure of Example 1, yielding about 283 g. of 1-(2-imino-l,1-dimethy1-2-phenylethy1)pyrrolidine, a pale yellow liquid, B.P. about 107-112 (0.2 mm.).

EXAMPLE 16 N -(2-I mino-I ,1 -Dimethyl-2-Phenylethyl) -N- M ethylbenzylamine PART A. 2- N-METHYLBENZYLAMINO -2METHYL PRGPIONITRILE A mixture of 170 g. of N-methylbenzylamine and 127 g. of acetonecyanohydrin is refluxed for three hours and then fractionated to give about 62 g. of 2-(N-methylbenzylamino)-2-methylpropionitrile, B.P. about l09-114 (0.2 mm.).

PART B. N-(2IMINO-1,1-DIl\IETHIL-2-PHENYLETHYL)- N-METHYLBENZYLAMINE An ethereal solution of 62 g. of material from Part A is reacted with 81 g. of phenyl lithium in ether and the product is isolated as in Example 1, giving about 63 g. of N-(Z-imino-1,l-dimethyl-2-phenylethyl)-N-methylbenzylamine, B.P. about 139-l44 (0.1 mm.).

EXAMPLE 17 N-(Z-Imino-I ,1 -Dimethyl-2-Phenylethyl) Diethylamine Following the procedure of Example 1, except for the substitution of 73 g. of a-diethylaminoisobutyronitrile for the a-piperidineisobutyronitrile employed therein, yields the product N-Z-imino-l,l-dirnethyl-Z-phenylethyl)-diethylamine.

6 EXAMPLE 1s 1-(1-Benzimidoylcyclohexyl)Piperidine PART A. l-PIPERIDINOCYCLOEIEXAN'ENETRILE Interaction of 138 g. of material from Part A with 83.5 g. of phenyl lithium in ether according to the procedure of Example 1 gives about 151 g. of l-(l-benzimidoylcyclohexyl) piperidine; M.P. about 85-89. After recrystallization from aqueous methanol, the purified material melts at about 88-89. I

EXAMPLE 19 1 -[1 (N -Acetylbenzimidoyl Cyclohexyl] Piperidine,

Hydrochloride A solution of 108 g. of material from Part B of Example 18 in 450 m1. of benzene is added to a cold solution of 32.5 g. of acetyl chloride in 400 m1. of benzene M.P. about 151-158".

and the resulting mixture is refluxed for three hours, cooled and filtered, yielding about 123.5 g. of material, Recrystallizations from butanone and methanol-ether give 1[-N-acetylbenzirnidoyl)cyclohexyl1piperidine, hydrochloride, having a melting point of about 159-161.

EXAMPLE 20 N-(Z-Imino-I -Methyl-1 ,2-Diphenylethyl)- Dimethylamine, Hydrochloride compounds of the following formula RI R ?l7 ""'i* Rlll wherein R is a member selected from the group consisting of hydrogen, lower alkyl, halogen, halomethyl, alkoxy, phenyloxy, hydroxy, amino and dialkylamino; R is a member selected from the group consisting ofhydrogen 7 alkanoyl, alkenoyl, sorboyl, phenacetyl, cinnamoyl, benzoyl, chlorobenzoyl, napthoyl, carbamyl, dialkylcarbamyl, lower alkane sulfonyl and benzenesulfonyl; R" and R' are individually members selected from the group consisting of lower alkyl and phenyl and together with the carbon to which they are joined R" and R are selected from the group consisting of cyclohexyl, cycloheptyl and cyclopentyl; B is a member selected from the group consisting of alkylamino, dialkylamino, (lower alkyl)phenyl (lower alkyl) amino, piperidino, pyrrolidino,N -alkylpiperazino and N -phenylpiperazino; and the pharmaceuticallyacceptable non-toxic acid-addition salts thereof.

2. 1-(2-imino-1,1-dimethy 1 -2 phenylethyDpiperidine, hydrochloride.

3. 1(2-acetylimino-1,1-dimethyl-2-phenylethyl) piperidine, hydrochloride.

4. 1-(1,1-dimethyl-2-phenaeetylimino-2 phenylethyl)- piperidino, hydrochloride.

7 5. 1-(1,1-dirnethyl-Z-methanesulfonylimino 2 phenylethyl)-piperidine, hydrochloride.

6. A probes for the preparation of a compound selected fromv the group consisting of compounds of the formula NE E ELLE

1km v wherein R is a member selected from the group consisting of hydrogen, lower alkyl, halogen, halomethyl, alkoxy, phenyloxy, hydroxy, amino a d dialkylamino; R" and R' are individually members selected from the group consisting of lower alkyl and phenyl and together with the carbon to which they are joined R" and R" are selected from the group consisting of cyclohcxyl, cycloheptyl and cyclopentyl; and B is a member sercted from the group consisting of alkylamino, dialkylarnuo, (lower alkyl)- phenyl (lower alkyDamino, piperidino, pyrrolidino, N alkylpiperazino and N phenylpiperazino; and the pharmaceutically-acceptable non-toxic acid-addition salts thereofrwhich comprises the steps of reacting a compound of the formula B with a nitrile of the formula I R! NO-t!l-B and subjecting the resulting complex to mild hydrolysis to provide the N-unsubstituted free base of the formula selected from the class consisting of acyl halide and acid anhydride and recovering the resulting N-acylated product.

No references cited. 

1. A COMPOUND SELECTED FROM THE CLASS CONSISTING OF COMPOUNDS OF THE FOLLOWING FORMULA
 6. A PROCESS FOR THE PREPARATION OF A COMPOUND SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS OF THE FORMULA 